Effects of parental overweight and obesity on offspring’s mental health: A meta-analysis of observational studies

Background Children of parents who were overweight/obese prior to pregnancy face a variety of neurodevelopmental challenges. The goal of this meta-analysis is to compile evidence about the impact of parental overweight/obesity on their children’s mental health. Methods The databases Cochrane Library, EMBASE, Pubmed, PsycINFO, and Web of Science were searched until May 2022. The pooled effect size was calculated using the fixed and random effect models. We also performed I2 index, subgroup analyses, sensitivity analyses, quality assessment, and publication bias analysis. The protocol was registered on the PROSPERO database (CRD42022334408). Results For maternal exposure (35 studies), both maternal overweight [OR 1.14 (95% CI 1.10,1.18)] and maternal obesity [OR 1.39 (95% CI (1.33, 1.45)] were significantly associated with offspring’s mental disorders. Maternal pre-pregnancy overweight/obesity increased the risk of attention-deficit/hyperactivity disorder (ADHD) [OR 1.55 (95% CI 1.42,1.70)], autism spectrum disorder (ASD) [OR 1.37 (95% CI 1.22,1.55)], cognitive/intellectual delay [OR 1.40 (95% CI 1.21,1.63)], behavioral problems [OR 1.50 (95% CI 1.35,1.66)] and other mental diseases [OR 1.30 (95% CI 1.23,1.37)]. For paternal exposure (6 studies), paternal obesity [OR 1.17 (95% CI 1.06, 1.30)] but not overweight [OR 1.03 (95% CI 0.95,1.11)] was significantly associated with offspring’s mental disorders. Conclusions Parental overweight/obesity might have negative consequences on offspring’s mental health and pre-pregnancy weight control is advised.


Introduction
The prevalence of mental illness is clearly on the rise. According to the Global Burden of Diseases 2019 report, there is no global indication of a decline in mental illnesses since 1990, placing them among the top 10 primary sources of burden globally [1]. A diverse set of genetic and/or environmental risk factors play an important role in the etiology of mental illness by altering brain structure and/or function. Notably, the incidence of parental obesity has been rising together with the prevalence of mental illness, suggesting a possible link between the two phenomena [2]. Studies have shown children born to obese mothers may have a higher risk of ASD and ADHD, as well as perform worse in terms of intellectual disability (ID) than children born to normal weight mothers. Paternal obesity may also negatively impact cognitive and behavioral outcomes in offspring [3][4][5]. The underlying mechanisms causing these laterlife detrimental consequences in offspring are not clear. Potential pathways whereby metabolized nutritional components may affect child development. Both maternal and paternal obesity can impact several processes involved in the conception, as well as intrauterine and postnatal development of the offspring [3,6].
Previous meta-analysis established a link between maternal obesity and offspring's neurodevelopment. All of them reported offspring exposed to maternal overweight/obesity, might raise the risk of psychiatric disorders such as ADHD, ASD, negative emotion, schizophrenia, and behavior problems [7][8][9][10][11][12]. But they seldom comprehensively assessed their offspring's mental health and failed to carefully check maternal weight exposure prior to pregnancy. Despite the equal prevalence of obesity in both sexes [13][14][15], the vast majority of research has focused on maternal nutritional influences on children during gestation and lactation. However, limited attention has been paid to the effect of paternal weight on offspring [16]. None of the previous meta analyses considered the effect of paternal overweight/obesity on offspring's mental health. Only one analyzed the relationship between paternal body mass index (BMI) and ASD in the offspring [9] and stated that paternal BMI has no association with offspring's ASD because of insufficient evidence. More importantly, a large number of studies on this topic have been published in recent years and have explored the effect of paternal BMI, with inconsistent outcomes [17][18][19].To better summarize the expanding research, we performed a meta-analysis to fully evaluate the association between parental obesity/overweight and offspring's mental health.
AND (mental illness) AND (case-control OR cohort study). We used truncations and wildcards to accommodate synonyms and variations. Additionally, we looked for further studies by manually scanning review papers that came up in our searches. Two authors (Zhang and Lin) checked reference lists to find research that would be possibly eligible for our inclusion criteria. The full search strategy can be found in S1 Table.

Study selection
Two authors screened records separately. First, titles and abstracts of articles were examined and full texts would be retrieved if necessary. Inclusion criteria:(1) Population: parents and their offspring;(2) Exposure: evaluated either the paternal or maternal pre-pregnancy weight status;(3) Outcome: addressed the mental health of offspring;(4) Study design: original observational study. Exclusion criteria:(1) Target population involved parents with mental disorder or children not born at full term;(2) The parental BMI used was not measured at pre-pregnancy; (3) The study reported continuous outcome data. Disagreements were resolved in a group discussion.

Data extraction
Data extraction was completed by two investigators (Zhang and Lin). The following information was extracted: (1) Basic research information about authorship and date of publication; (2) Cohort characteristics included study design, country, sample size, cohort name and covariates; (3) Exposure information included parental weight status and BMI criteria; (4) Outcome information included the offspring's age at evaluation, neurodevelopmental outcomes and their diagnostic methods (5) Odds Ratios(OR), Risk Ratio (RR), or Hazard Ratio(HR) with corresponding 95% confidence interval (CI) was also extracted from each included study.

Quality assessment
The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the quality of the included studies, which is recommended by Cochrane Collaboration [21]. We regarded studied as high quality when they had 6 or more stars.

Statistical analysis
In this meta-analysis, the following issues with repeated measurements in the same sample should be taken into account: (1) Data from studies with two cohorts were analyzed as independent samples; (2) The meta-analysis only included studies reporting separate data for prepregnancy overweight and obesity;(3)When neurodevelopment was examined using several tests within the same cohort, we took into account the values for all of the tests and if a test provided a total score value, this was the only value taken into account for the pooled estimate; (4) When several estimates were reported within the same study, the most adjusted model was used for the pooled estimate.
For all outcomes, estimates were converted into OR (where possible) and pooled OR were estimated using the fixed and random effect models. Heterogeneity was assessed using the I 2 statistic. I 2 values of <25%, 25-50% and >50% usually correspond to small, medium and large heterogeneity, respectively [22].
The following subgroup analyses were conducted: (1) Analyze the relationship between parental BMI pre-pregnancy categories and the risk of mental illness in offspring; (2) Analyze the relationship between maternal BMI pre-pregnancy categories and the risk of specific outcomes (ADHD, ASD, cognitive/intellectual delay, behavioral problems, and other mental diseases including schizophrenia, negative emotions, psychomotor development, etc.). The presence of publication bias was quantified using the Begg's test and Egger's test.
We performed three kinds of sensitivity analyses to examine the robustness of our results: (1) We defined higher-quality studies as those that had high scores on the quality measure; (2) We grouped studies by their study design;(3) We removed studies one by one to assess the robustness of the summary estimates. All statistical analyses were conducted using Stata, version 16.0 (Stata Corp, College Station, TX, USA).

Literature search
A total of 22 611 records were identified in the above databases (Fig 1). After removing duplicates (4 530), 18 081 records were yielded. Of these, most records were removed from the title (n = 17 864) and abstract screening (135) because they were non-relevant study designs or further duplicates. Besides, 22 additional articles were found during manual searching from the reference lists of relevant records. Thus, 104 articles were considered for full-text screening, and 69 were excluded, giving final 35 studies included in the meta-analysis.

PLOS ONE
Parental overweight/obesity and offspring's mental health their analysis two cohorts. The included samples ranged from 197 to 620 795, belonging to 39 cohorts started between 1959 and 2008. For the geographical area of included studies, 18 studies were from the America, 14 from Europe, 2 from Australasia and 1 from Asia. There were 30 high quality studies and 5 low quality studies.

Risk of any mental illness
We pooled the risk of any mental illness in offspring exposed to maternal and paternal overweight and obesity separately. For overweight mothers, there were 14% higher odds of having a child with any adverse mental outcome (OR, 1.14; 95% CI, 1.  Table 3).

Risk of specific mental illness
We performed subgroup analyses according to specific offspring outcomes. The detailed information can be found in Table 3 and Figs 3-7.

Publication bias
There was no evidence of publication bias according to Begg's test and Egger's test (all P>0.05) except the pooled analysis which show inconclusive evidence for an association between paternal overweight and offspring mental illnesses.

Sensitivity analysis
Sensitivity analysis showed the results of the main analyses are robust. Studies with cohort study design produced an overall OR that was lower than those with case-control design. Slightly attenuated OR was observed for those studies ranked as having a lower quality score than those ranked as having a higher quality score (Table 4). We also investigated the influence of a single study on the overall risk estimate by performing leave-one-out analysis. The combined ORs of overall risk estimates were consistent and without apparent fluctuation (S3 Table).

Discussion
The findings of this meta-analysis are consistent with previous reviews that revealed a negative link between maternal pre-pregnancy overweight/obesity and the neurodevelopmental outcomes in offspring. Several inconsistencies should also be mentioned. First, to date, this is the first comprehensive meta-analysis not only investigated the effect of maternal overweight/obesity on offspring mental health but also fathers. Although far fewer studies have investigated paternal exposure than maternal, to some extent, we still conclude that paternal obesity has adverse effects on the neurodevelopment of their offspring. Second, for maternal weight

PLOS ONE
Parental overweight/obesity and offspring's mental health

PLOS ONE
Parental overweight/obesity and offspring's mental health exposure, we excluded studies that examined weight during pregnancy because of the neurological effects of gestational weight gain (GWG) on offspring. Evidence showed that whether GWG is insufficient or excessive may be important to fetal neurodevelopment [58][59][60]. However, the degree to which GWG and pre-pregnancy obesity independently or synergistically relate to an increased risk of offspring's mental illnesses is not clear [61,62]. Third, because we adhere to strict definitions of study design, the estimates of effect sizes are more accurate than they would be with weaker study designs, including cross-sectional studies. Forth, the included studies come from heterogeneous samples, countries, measures and designs so the effect size in the main analysis showed appropriate representativeness. Multiple mechanisms have been proposed to explain the impact of maternal obesity on the offspring neurodevelopment. To our knowledge, obesity during pregnancy changes neuroendocrine, metabolic and inflammatory status [4].The increased cytokines, oxidative stress, and circulating hormones disorder "mother-placenta-fetus" system [63,64]and the composition of lactational milk composition [65], resulting in potential changes to child's neurodevelopment which in turn influences behaviour, emotion and cognition [66]. In addition to neuroinflammation, altered neuronal plasticity(brain-derived neurotrophic factor, notch signaling genes, proliferation of neuronal progenitor cells, abnormal synaptic stability) [67], impaired reward circuitry(dopaminergic and serotonergic signaling) [68] and dysregulated brain metabolism (leptin, insulin and oxytocin) and likely contributors. The alterations in the gut microbiome's composition are another mechanism that has recently received attention [69]. Microbial metabolites may affect neuroendocrine regulation and brain development via passing through the placenta, vertically transmitting and lactation [65]. However, the detailed dynamics remain poorly understood.

PLOS ONE
The mechanisms explaining how the father may affect the neurodevelopment of offspring are still under debate [70].Obesity causes a variety of symptoms in men, including changes in their gut microbiome, hormone levels, and sperm health, which can lead to abnormalities in  fertilization and embryonic development [71][72][73]. Additionally, seminal plasma has a distinct microbiome that can be altered by a high-fat diet(HFD), which means it can indirectly affect the offspring's neurodevelopment and later brain function by passing along information about the father's eating habits and metabolic condition [74].
Moreover, maternal and paternal obesity predispose offspring to poor neurodevelopment by epigenetic molecular mechanism, which is studied intensively in the field of neurobiology in animals [63]. The underlying molecular mechanisms involve DNA methylation, post-translational modifications of chromatin and/or histone proteins, and small noncoding RNAs (sncRNAs) alterations, which change the expression of genes involved in neuroplasticity [3].  Among the classical epigenetic mechanisms, DNA methylation is an attractive target for research. It has been reported that offspring of obese females exhibited DNA hypomethylation in gene promoters including those encoding proteins involved in dopamine uptake, and serotonergic and opioid signaling [3,75,76] and may be associated with the decreased folic acid in obese pregnant women [67]. Zhou et al. report that paternal HFD results in cognitive impairments in the F1 potentially due to the increased methylation of the BDNF gene promoter transmitted by F0 spermatozoa [77]. The recent clinical research found a link between paternal BMI and altered DNA methylation in cord blood nucleated cells, indicating that there are environment-sensitive parts of the sperm epigenome that respond to food and may transmit an 'epigenomic map' that impacts offspring development [78]. Furthermore, sncRNAs have been hypothesized as another pathway of epigenetic transfer, particularly through the paternal line. These sperm-derived RNAs appear to be sensitive to a diverse range of psychological and physiological conditions, including stress exposure and nutrition, and are able to transmit intergenerational information through the paternal lineage [70,72,73]. Obesity-caused hyperglycemia, insulin resistance, and a proinflammatory lipotoxic environment could be the immediate source of such epigenetic changes, resulting in developmental brain problems in offspring [3].
Here, we detail the limitations that might influence the combined results. First, lack of resources meant that we excluded papers that were not in English and studies with continuous variables. Besides, it was very possible that studies with bad outcomes were unlikely to be published. Second, the exposure and outcome factors might have resulted in disparate results. The parental weight groupings and diagnostic criteria of neurodevelopment were variable, which may affect the results and contribute to the heterogeneity across several risk factors. Third, all the identified studies came from observational settings and were therefore subjected to confounding bias. Forth, the limited number of studies investigated fathers (only 6 studies) might affect the combined results. Also, 91% included studies were conducted in the America (51%) and Europe (40%), which limit generalizability to other populations across the world. Future studies should be performed in more countries outside of America and Europe.

Conclusion
We found that the most recent evidence indicates the detrimental connections between parental pre-pregnancy overweight/obesity and offspring mental health. To reduce the incidence of mental problems in children, it may be prudent to conduct measures targeted at avoiding overweight and obesity in both mother and father. However, given the constraints discussed above, more research employing a range of study designs such as sibling comparison, children-oftwins designs, and within-family Mendelian randomization would be helpful in identifying the magnitude of the overall impact size. Also, the recent study showed grandmother underweight prior to pregnancy is associated with an increased risk of ADHD among grandchildren independent of maternal pre-pregnancy weight status, future work should focus on discovering mechanisms linking weight status and offspring mental health across generations.